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US 6,306,860 B1Granted
2,5-pyridinedicarboxylic acid derivatives
AssigneeDong Wha Pharm. Co., Ltd.
InventorsSung Joon Yoon, Sang Wook Lee, Hyeong Su Sim, Yong Kyun Park, Wang Yong Yang, Jong Woo Kim, Jae Jin Han, Je In Yoon, Sang Jin Park, Hee Jeoung Park, Dong Hyuk Sin, Hwan Bong Chang
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Abstract
Anti-viral agents of formula (1) have been identified. Their preparation method is described. These 2,5-pyridinedicarboxylic acid derivatives or their pharmaceutically acceptable salts are useful in countering the proliferation of viruses such as hepatitis B virus and human immunodeficiency virus.
Claims15
A 2,5-pyridinedicarboxylic acid derivative, and pharmaceutically acceptable salts thereof, of the formula 1
- wherein
- R1 is selected from the group consisting of:
- a hydroxy group,
- a straight or branched alkyl group of 1 to 6 carbon atoms,
- a cycloalkyl group of 3 to 6 carbon atoms unsubstituted or substituted with an alkyl group of 1 to 3 carbon atoms,
- an alkyl group of 1 to 3 carbon atoms substituted with a cycloalkyl group of 3 to 6 carbon atoms,
- a straight or branched hydroxyalkyl group of 1 to 6 carbon atoms,
- a straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms,
- a straight or branched alkoxy group of 1 to 4 carbon atoms,
- a hydroxyalkoxy group of 2 to 4 carbon atoms,
- a straight or branched alkoxyalkyl group of 2 to 6 carbon atoms,
- a dialkoxyalkyl group of 3 to 6 carbon atoms,
- a dialkylamino group of 2 to 4 carbon atoms,
- an acetylamino group,
- a vinyl group, and
- a saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being unsubstituted or substituted with same or different substituents selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, a phenyl group, a carbamoyl group and a hydroxy group;
- R2 is selected form the group consisting of:
- a hydrogen atom,
- a phenyl group,
- a straight or branched alkyl group of 1 to 4 carbon atoms,
- a straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, and
- an alkoxyalkyl group of 2 to 4 carbon atoms;
- R3 is selected form the group consisting of:
- a 2-hydroxyethyl group, and
- a 3-amino-2-pyridyl group having the formula
- in which Q is a hydrogen atom or a straight or branched alkyl group of 1 to 4 carbon atoms;
- and
- n is 0 to 4.
25 more elements
A method for treating a disease caused by a virus, wherein the virus is hepatitis B virus or human immunodeficiency virus comprising administering a patient in need thereof an effective amount of compound, and pharmaceutical pharmaceutically acceptable salts thereof, having the formula 1
- wherein
- R1 is selected from the group consisting of:
- a hydroxy group,
- a straight or branched alkyl group of 1 to 6 carbon atoms,
- a cycloalkyl group of 3 to 6 carbon atoms unsubstituted or substituted with an alkyl group of 1 to 3 carbon atoms,
- an alkyl group of 1 to 3 carbon atoms substituted with a cycloalkyl group of 3 to 6 carbon atoms,
- a straight or branched hydroxyalkyl group of 1 to 6 carbon atoms,
- a straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms,
- a straight or branched alkoxy group of 1 to 4 carbon atoms,
- a hydroxyalkoxy group of 2 to 4 carbon atoms,
- a straight or branched alkoxyalkyl group of 2 to 6 carbon atoms,
- a dialkoxyalkyl group of 3 to 6 carbon atoms,
- a dialkylamino group of 2 to 4 carbon atoms,
- an acetylamino group,
- a vinyl group, and
- a saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being unsubstituted or substituted with same or different substituents selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, a phenyl group, a carbamoyl group and a hydroxy group;
- R2 is selected form the group consisting of:
- a hydrogen atom,
- a phenyl group,
- a straight or branched alkyl group of 1 to 4 carbon atoms,
- a straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, and
- an alkoxyalkyl group of 2 to 4 carbon atoms;
- R3 is selected form the group consisting of:
- a 2-hydroxyethyl group, and
- a 3-amino-2-pyridyl group having the formula
- in which Q is a hydrogen atom or a straight or branched alkyl group of 1 to 4 carbon atoms;
- and
- n is 0 to 4.
25 more elements
A process for preparing 2,5-pyridinedicarboxylic acid derivative of formula 1
- wherein
- R1 is selected from the group consisting of:
- a hydroxy group,
- a straight or branched alkyl group of 1 to 6 carbon atoms,
- a cycloalkyl group of 3 to 6 carbon atoms unsubstituted or substituted with an alkyl group of 1 to 3 carbon atoms,
- an alkyl group of 1 to 3 carbon atoms substituted with a cycloalkyl group of 3 to 6 carbon atoms,
- a straight or branched hydroxyalkyl group of 1 to 6 carbon atoms,
- a straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms,
- a straight or branched alkoxy group of 1 to 4 carbon atoms,
- a hydroxyalkoxy group of 2 to 4 carbon atoms,
- a straight or branched alkoxyalkyl group of 2 to 6 carbon atoms,
- a dialkoxyalkyl group of 3 to 6 carbon atoms,
- a dialkylamino group of 2 to 4 carbon atoms,
- an acetylamino group,
- a vinyl group, and
- a saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being unsubstituted or substituted with same or different substituents selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, a phenyl group, a carbamoyl group and a hydroxy group;
- R2 is selected form the group consisting of:
- a hydrogen atom,
- a phenyl group,
- a straight or branched alkyl group of 1 to 4 carbon atoms,
- a straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, and
- an alkoxyalkyl group of 2 to 4 carbon atoms;
- R3 is selected form the group consisting of:
- a 2-hydroxyethyl group, and
- a 3-amino-2-pyridyl group having the formula
- in which Q is a hydrogen atom or a straight or branched alkyl group of 1 to 4 carbon atoms;
- and
- n is 0 to 4,
- comprising the step of:
- reacting nicotinic acid ester derivatives of formula 2
- with an amine compound of formula 3
28 more elements
A process for preparing 2,5-pyridinedicarboxylic acid derivative of formula 1a
- wherein
- R1 is selected from the group consisting of:
- a hydroxy group,
- a straight or branched alkyl group of 1 to 6 carbon atoms,
- a cycloalkyl group of 3 to 6 carbon atoms unsubstituted or substituted with an alkyl group of 1 to 3 carbon atoms,
- an alkyl group of 1 to 3 carbon atoms substituted with a cycloalkyl group of 3 to 6 carbon atoms,
- a straight or branched hydroxyalkyl group of 1 to 6 carbon atoms,
- a straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms,
- a straight or branched alkoxy group of 1 to 4 carbon atoms,
- a hydroxyalkoxy group of 2 to 4 carbon atoms,
- a straight or branched alkoxyalkyl group of 2 to 6 carbon atoms,
- a dialkoxyalkyl group of 3 to 6 carbon atoms,
- a dialkylamino group of 2 to 4 carbon atoms,
- an acetylamino group,
- a vinyl group, and
- a saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being unsubstituted or substituted with same or different substituents selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, a phenyl group, a carbamoyl group and a hydroxy group;
- R2 is selected form the group consisting of:
- a hydrogen atom,
- a phenyl group,
- a straight or branched alkyl group of 1 to 4 carbon atoms,
- a straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, and
- an alkoxyalkyl group of 2 to 4 carbon atoms;
- Q is selected from the group consisting of:
- a hydrogen atom and a straight or branched alkyl group of 1 to 4 carbon atoms;
- and
- n is 0 to 4,
- comprising the step of:
- reacting a compound of formula 2a
- with an amine compound of formula 3
26 more elements
A process for preparing 2,5-pyridinedicarboxylic acid derivative of formula 1a
- wherein
- R1 is selected from the group consisting of:
- a hydroxy group,
- a straight or branched alkyl group of 1 to 6 carbon atoms,
- a cycloalkyl group of 3 to 6 carbon atoms unsubstituted with an alkyl group of 1 to 3 carbon atoms,
- an alkyl group of 1 to 3 carbon atoms substituted with a cycloalkyl group of 3 to 6 carbon atoms,
- a straight or branched hydroxyalkyl group of 1 to 6 carbon atoms,
- a straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms,
- a straight or branched alkoxy group of 1 to 4 carbon atoms,
- a hydroxyalkoxy group of 2 to 4 carbon atoms,
- a straight or branched alkoxyalkyl group of 2 to 6 carbon atoms,
- a dialkoxyalkyl group of 3 to 6 carbon atoms,
- a dialkylamino group of 2 to 4 carbon atoms,
- an acetylamino group,
- a vinyl group, and
- a saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being unsubstituted or substituted with same or different substituents selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, a phenyl group, a carbamoyl group and a hydroxy group;
- R2 is selected form the group consisting of:
- a hydrogen atom,
- a phenyl group,
- a straight or branched alkyl group of 1 to 4 carbon atoms,
- a straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, and
- an alkoxyalkyl group of 2 to 4 carbon atoms;
- Q is selected from the group consisting of:
- a hydrogen atom and a straight or branched alkyl group of 1 to 4 carbon atoms;
- and
- n is 0 to 4,
- comprising the step of:
- (a) reacting nicotinic acid ester derivative including nitropyridyl group of formula 4
- with an amine compound of formula 3
- to form an intermediate of formula 6
- (b) reducing the intermediate or reductively alkylating after reducing the intermediate to form the compound of formula 1a.
28 more elements
A process for preparing 2,5-pyridinedicarboxylic acid derivative of formula 1a
- wherein
- R1 is selected from the group consisting of:
- a hydroxy group,
- a straight or branched alkyl group of 1 to 6 carbon atoms,
- a cycloalkyl group of 3 to 6 carbon atoms unsubstituted or substituted with an alkyl group of 1 to 3 carbon atoms,
- an alkyl group of 1 to 3 carbon atoms substituted with a cycloalkyl group of 3 to 6 carbon atoms,
- a straight or branched hydroxyalkyl group of 1 to 6 carbon atoms,
- a straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms,
- a straight or branched alkoxy group of 1 to 4 carbon atoms,
- a hydroxyalkoxy group of 2 to 4 carbon atoms,
- a straight or branched alkoxyalkyl group of 2 to 6 carbon atoms,
- a dialkoxyalkyl group of 3 to 6 carbon atoms,
- a dialkylamino group of 2 to 4 carbon atoms,
- an acetylamino group,
- a vinyl group, and
- a saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being unsubstituted or substituted with same or different substituents selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, a phenyl group, a carbamoyl group and a hydroxy group;
- R2 is selected form the group consisting of:
- a hydrogen atom,
- a phenyl group,
- a straight or branched alkyl group of 1 to 4 carbon atoms,
- a straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, and
- an alkoxyalkyl group of 2 to 4 carbon atoms;
- Q is selected from the group consisting of:
- a hydrogen atom and a straight or branched alkyl group of 1 to 4 carbon atoms;
- and
- n is 0 to 4,
- comprising the steps of:
- (a) reacting nicotinic acid ester derivative including nitropyridyl group of formula 5
- with a amine compound of formula 3
- to form a intermediate of formula 6
- (b) reducing the intermediate or reductively alkylating after reducing the intermediate to form the compound of formula 1a.
28 more elements
A process for preparing nicotinic acid derivative of formula 2a
- wherein Q is selected from the group consisting of:
- a hydrogen atom and a straight or branched alkyl group of 1 to 4 carbon atoms,
- comprising the steps of:
- (a) reacting 5-(methoxycarbonyl)-2-pyridinecarboxylic acid of formula 7
- with an acid chloride derivative to form an acid anhydride derivative;
- (b) reacting the acid anhydride derivative with 1-(3-nitro-2-pyridyl)piperazine of formula 8
- to form a nicotinic acid ester derivative of formula 4
- (c) reducing the nicotinic acid ester derivative to obtain an aminopyridyl group derivative of formula 9
- (d) reductively alkylating the aminopyridyl group derivative in the presence of a reducing agent under an acidic condition to obtain a nicotinic acid ester derivative of formula 2b
- (e) hydrolyzing the nicotinic acid ester derivative of formula 2b to give nicotinic acid derivative of the formula 2a .
7 more elements
A process for preparing ester derivative of the following formula 2b
- wherein Q is selected from the group consisting of:
- a hydrogen atom and a straight or branched alkyl group of 1 to 4 carbon atoms, comprising the step of:
- reacting 5-(methoxycarbonyl )-2-pyridinecarboxylic acid of formula 7
- with 1-[3-(alkylamino)-2-pyridyl]piperazine of formula 10
1 more element
Nicotinic acid ester derivative of a formula 2
- wherein R3 is selected form the group consisting of:
- a 2-hydroxyethyl group, and
- a 3-amino-2-pyridyl group having the formula
- in which Q is a hydrogen atom or a straight or branched alkyl group of 1 to 4 carbon atoms.
1 more element
Dependencies are inferred from the claim text.